Genistein exhibits therapeutic potential for PCOS mice <i>via</i> the ER-Nrf2-Foxo1-ROS pathway

Luo, Man; Zheng, Lianwen; Wang, Yu-Si; Huang, Ji-Cheng; Yang, Zhan-Qing; Yue, Zhan‐Peng; Guo, Bin

doi:10.1039/d1fo00684c

Cited by 33 publications

(32 citation statements)

References 30 publications

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“…Melatonin might withhold the expression of FOXO1, whose repression accelerated the defect in the differentiation program in melatonin-treated ESCs, while replenishment of rNOTCH1 ameliorated the impediment of melatonin on FOXO1, but this amelioration was disrupted by NRF2 inhibitor ML385. Moreover, previous study had identified FOXO1 as a direct downstream target of NRF2 [16]. Together these observations suggest that NRF2 acts as downstream of NOTCH1 signaling pathway to mediate the regulation of melatonin on FOXO1.…”

Section: Discussionsupporting

confidence: 61%

Melatonin modulates endometrial decidualization via NOTCH1–NRF2–FOXO1–GSH pathway

Jin

Wang

Huang

et al. 2023

Biology of Reproduction

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Melatonin is important for oocyte maturation, fertilization, early embryonic development and embryo implantation, but less knowledge is available regarding its role in decidualization. The present study found that melatonin did not alter the proliferation of human endometrial stromal cells (ESCs) as well as cell cycle progress, but suppressed stromal differentiation after binding to the MTNR1B receptor which was visualized in decidualizing ESCs. Further analysis evidenced that application of melatonin resulted in the diminishment for NOTCH1 and RBPJ expression. Supplementation of rNOTCH1 counteracted the impairment of stromal differentiation conferred by melatonin, while addition of NOTCH signaling pathway inhibitor DAPT aggravated the differentiation progress. Meanwhile, melatonin might restrain the expression and transcriptional activity of NRF2 whose blockage accelerated the fault of stromal differentiation under the context of melatonin, but this restraint was subsequently ameliorated by rNOTCH1. FOXO1 was identified as a downstream target of melatonin in decidualization. Repression of NRF2 antagonized the retrieval of rNOTCH1 on aberrant FOXO1 expression elicited by melatonin. Moreover, melatonin brought about the occurrence of oxidative stress accompanied by an obvious accumulation of intracellular ROS, and significant reduction of GSH content as well as enzymatic activities of GPX and GR, whereas supplementation of rNOTCH1 improved above effectiveness, but this improvement was disrupted by the blockage of NRF2 and FOXO1. Furthermore, addition of GSH rescued the defect of stromal differentiation by melatonin. Collectively, melatonin might impair endometrial decidualization through restraining the differentiation of ESCs dependent on NOTCH1-NRF2-FOXO1-GSH pathway after binding to MTNR1B receptor.

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Section: Discussionsupporting

confidence: 61%

Melatonin modulates endometrial decidualization via NOTCH1–NRF2–FOXO1–GSH pathway

Jin

Wang

Huang

et al. 2023

Biology of Reproduction

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“…Meanwhile, genistein increased the levels of Nrf2, which is vital to the GSH system [132][133][134]. Genistein administration induced Nrf2 enhancement by activation/phosphorylation of keap1, sirt1, MAPK-ERK1/2, PKC, and estrogen receptor in other cells or tissues, such as: hippocampal tissue, hypothalamic paraventricular nucleus, ovary, and Caco-2 cells [131,[135][136][137]. However, it is unclear why genistein upregulates the levels of Nrf2 in the myocardium.…”

Section: Glutathione System Activatormentioning

confidence: 99%

Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis

Tan

Yin

et al. 2023

Cell Death Dis

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The glutathione (GSH) system is considered to be one of the most powerful endogenous antioxidant systems in the cardiovascular system due to its key contribution to detoxifying xenobiotics and scavenging overreactive oxygen species (ROS). Numerous investigations have suggested that disruption of the GSH system is a critical element in the pathogenesis of myocardial injury. Meanwhile, a newly proposed type of cell death, ferroptosis, has been demonstrated to be closely related to the GSH system, which affects the process and outcome of myocardial injury. Moreover, in facing various pathological challenges, the mammalian heart, which possesses high levels of mitochondria and weak antioxidant capacity, is susceptible to oxidant production and oxidative damage. Therefore, targeted enhancement of the GSH system along with prevention of ferroptosis in the myocardium is a promising therapeutic strategy. In this review, we first systematically describe the physiological functions and anabolism of the GSH system, as well as its effects on cardiac injury. Then, we discuss the relationship between the GSH system and ferroptosis in myocardial injury. Moreover, a comprehensive summary of the activation strategies of the GSH system is presented, where we mainly identify several promising herbal monomers, which may provide valuable guidelines for the exploration of new therapeutic approaches.

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“…Indeed, the increased expression of CYP11A1 and HSD3B1 may explain the increased level of P after TP treatment. A possible reason for the increase of the CYP19A1 gene expression is that the abnormal increase of androgens triggers the body's own regulatory mechanism, and by increasing the expression of the CYP19A1 gene, the excess androgen is converted into E 2 [42].…”

Section: Discussionmentioning

confidence: 99%

Fetuin B alleviates testosterone propionate-induced oxidative stress and mitochondrial dysfunction in KGN cells by upregulating the TGFR2/SMAD3 pathway

Gao

Zheng

et al. 2022

Preprint

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Background Polycystic ovary syndrome (PCOS) is one of the most common reproduction and endocrine disorders. Patients with abnormal follicle growth develop ovulation disorders and amenorrhea, and eventually infertility. The role of Fetuin-B (FETUB), one of the differentially expressed proteins (DEPs) in follicular fluid (FF) of PCOS patients, in pathogenesis of PCOS was not clearly clarified. Methods In this study, we performed iTRAQ-based quantitative proteomic analysis on FF collected from non-PCOS healthy controls and PCOS patients to identify DEPs. In addition, KGN cells treated with testosterone propionate (TP) were used as a model of hyperandrogenism in vitro to investigate the regulatory effects of the selected DEP, FETUB, on cellular processes in KGN cells and its molecular mechanism by detecting steroid hormone secretion, measuring indicators of oxidative stress (OS), mitochondria functions and apoptosis and characterizing the FETUB-altered downstream signaling. Results We found that supplementation with recombinant FETUB could significantly restore the total antioxidant capacity and activity of antioxidant enzymes, which were reduced by treatment with TP. Additionally, FETUB restored the secretory and mitochondrial functions in TP-impaired KGN cells and reduced their apoptosis. Furthermore, our study revealed that FETUB could bind with transforming growth factor beta receptor 2 (TGFR2) on the cell membrane of KGN cells and promote phosphorylation of SMAD3, which had a therapeutic effect against tissue injury and inflammation. And the protective effect of FETUB on TP-treated KGN cells was inhibited by pre-treatment with SB431542 and SIS3, selective inhibitors of TGFR2 and SMAD3, respectively. Conclusions These results indicate that FETUB may protect TP-treated KGN by alleviating OS and mitochondrial dysfunction via the TGFR2-mediated SMAD pathway. Data are available via ProteomeXchange with identifier PXD036531

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Genistein exhibits therapeutic potential for PCOS mice via the ER-Nrf2-Foxo1-ROS pathway

Abstract: Polycystic ovarian syndrome (PCOS) is a complex endocrinopathy in women of reproductive age and the main cause of female infertility, but there is no universal drug for PCOS therapy. As...

Cited by 33 publications

References 30 publications

Melatonin modulates endometrial decidualization via NOTCH1–NRF2–FOXO1–GSH pathway

Melatonin modulates endometrial decidualization via NOTCH1–NRF2–FOXO1–GSH pathway

Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis

Fetuin B alleviates testosterone propionate-induced oxidative stress and mitochondrial dysfunction in KGN cells by upregulating the TGFR2/SMAD3 pathway

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